Biology subjects

Hilgert, E.

Publications and source records attributed to Hilgert, E..

3 recordsLinked to original sources

bioRxiv2024

RUVBL1 and RUVBL2 are druggable MYCN regulators in neuroblastoma.

High-risk neuroblastoma is characterized by MYCN amplification and high MYCN or MYC gene expression. These patients have a poor prognosis and there is an urgent need for more effective drugs. While strategies to develop inhibitors that directly target the MYC proteins have remained largely unsuccessful, recent preclinical studies have identified ATR, a key protein of the DNA damage response, as a promising alternative therapeutic target. Here we identified a strong RUVBL1 and RUVBL2 signature in transcriptomics data derived from different MYCN-driven mice tumors treated with ATR inhibitors. The RUVBL proteins form a complex with ATPase activity that has broad cellular functions and we demonstrate that pharmacological inhibition of this protein complex results in a strong reduction of MYC signaling, cell cycle arrest, DNA damage and apoptosis. We confirmed the association with MYCN and identified the RUVBL genes as independent prognosticators in human primary neuroblastoma data.

cancer biology↗

bioRxiv2024

5UTR translational inhibition of neuroblastoma dependency factors using the CR-1-31-B rocaglate

Current therapies for neuroblastoma are often ineffective and survivors suffer from severe long-term therapy related side-effects, underscoring the need for identification of novel drugging strategies. We performed an in-depth evaluation of phenotypic and molecular responses following exposure of neuroblastoma cells to the rocaglate CR-1-31-B, scrutinizing its mode-of-action through integrative ribosome footprinting and shotgun proteome profiling. We could show that CR-1-31-B significantly reduces tumor growth in vivo without apparent toxicity. By means of combined ribosome footprinting and transcriptome analysis we uncovered that CR-1-31-B treatment downregulates translation efficiencies of several major neuroblastoma dependencies including MYCN, CCND1 and ALK as well as factors involved in the G2/M checkpoint. Upregulated targets are enriched for oxidative phosphorylation pathway components and DNA repair. At the proteome level, CR-1-31-B imposed downregulation of a FOXM1 driven signature, including the FOXM1 target gene TPX2. We show that neuroblastoma cells are dependent on TPX2 for growth and DNA repair and further demonstrate enhanced CHK1 sensitivity upon TPX2 knockdown. Next, we also observed synergistic effects of CHK1 inhibition with CR-1-31-B. In conclusion, our data support CR-1-31-B as a potent novel therapeutic agent in neuroblastoma, in particular in combination with DNA damage or replication stress inducing agents.

cancer biology↗

bioRxiv2023

MOXD1 is a gate-keeper of organ homeostasis and functions as a tumor-suppressor in neuroblastoma

Neuroblastoma is a childhood cancer believed to result from dysfunctional development. Its origin during embryogenesis remains poorly understood. The lack of appropriate models has hindered in-depth mapping of tumor-driving events. Here, we identify a novel tumor-suppressor gene that predicts poor survival in high-risk disease, by applying bulk and single cell RNA sequencing data of neuroblastoma and human fetal adrenal glands. Trunk neural crest-specific MOXD1 discriminates cell populations during normal and tumor development, with implications for deciphering neuroblastoma cell origin. We created an embryonic conditional knockout model and show that cell type-specific loss of MOXD1 leads to disrupted organ homeostasis and failed adrenal gland formation, home for neuroblastoma. We show that MOXD1 is a tumor suppressor gene in zebrafish, chick, and mice in vivo models. One-Sentence SummaryNeural crest-specific MOXD1 is a de novo tumor-suppressor gene in childhood cancers arising during embryogenesis.

cancer biology↗